The cyclic tetradecapeptide somatostatin-14 (SRIF) was originally isolated from the hypothalamus and characterized as a physiological inhibitor of growth hormone (GH) release from the anterior pituitary. It was characterized by Guillemin et al. and was described in U.S. Pat. No. 3,904,594. This tetradecapeptide has a bridging or cyclizing bond between the sulfhydryl groups of the two cysteinyl amino acid residues in the 3- and 14-positions. SRIF affects multiple cellular processes and is also known to inhibit the growth of certain tumors. The analog [D-Trp8]-SRIF, having the amino acid sequence: (cyclo 3-14)H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH, was disclosed in U.S. Pat. No. 4,372,884 and stated to have many times greater potency to inhibit release of GH than SRIF.
SRIF induces its biological effects by interacting with a family of membrane-bound structurally similar receptors. Five SRIF receptors have been cloned and are referred to as SSTR1-5. All five receptors bind SRIF and SRIF-28 with high affinity. Selective agonists at SSTR2 and SSTR5 have been identified and used to reveal distinct functions of these receptors. These two receptors are believed to be the predominant subtypes in peripheral tissues. SSTR2 is believed to mediate the inhibition of growth hormone, glucagon and gastric acid secretion. U.S. Pat. No. 5,846,934 describes analogs which are stated to have some specificity for SSTR2. Octreotide, an agonist, shows some specificity for SSTR2 (see Yang et al., 1998, PNAS USA 95: 10836). In contrast, SSTR5 appears to be primarily involved in the control of insulin and amylase release. International Publication No. WO 97/11962 described analogs which are stated to have some specificity for SSTR5. SSTR3 mediates inhibition of gastric smooth muscle contraction. U.S. Pat. No. 6,579,967 discloses somatostatin analogs which are specific to SSTR3, the disclosure of which is incorporated herein by reference. SSTR4 is found in the pituitary, lungs, GI tract, kidneys, and in certain tumors to the substantial exclusion of the other SRIF receptors; it is believed to be activated upon binding by SRIF. U.S. published Patent Application No. 2002/0137676 discloses methods for treatment of endothelial cells using somatostatin receptor-selective ligands which are specific either to SSTR1 or SSTR4. U.S. Pat. Nos. 5,750,499 and 7,019,109 disclose somatostatin peptide analogs which are selective for SSTR1, the disclosures of which are incorporated herein by reference. Published U.S. Patent Application No. 2005/0245438 discloses receptor-selective somatostatin peptide analogs which are specific to SSTR4. These overall findings indicate that different receptor subtypes mediate distinct functions of SRIF in the body.
Somatostatin receptors are expressed in pathological states, particularly in neuroendocrine tumors of the gastrointestinal tract. Most human tumors originating from the somatostatin target tissue have conserved their somatostatin receptors. It was first observed in growth hormone producing adenomas and TSH-producing adenomas; about one-half of endocrine inactive adenomas display somatostatin receptors. Ninety percent of the carcinoids and a majority of islet-cell carcinomas, including their metastasis, usually have a high density of somatostatin receptors. However, only 10 percent of colorectal carcinomas and none of the exocrine pancreatic carcinomas contain somatostatin receptors. The somatostatin receptors in tumors can be identified using in vitro binding methods or using in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastasis in the patients. Because somatostatin receptors in gastroenteropancreatic tumors are functional, their identification can be used to assess the therapeutic efficacy of an analog to inhibit excessive hormone release in the patients.
Somatostatin peptide antagonists that bind strongly to SSTR2, while at the same time showing only minimal propensity for binding to the other 4 receptors, would be valuable to have. Thus, the search has continued for such somatostatin peptide antagonists which are highly selective for SSTR2 but are not internalized into cells.